Psychotropic piperidinylmethyl benzodioxans

ABSTRACT

The compounds ##STR1## in which Z is ##STR2## where R 4  is --H or alkyl; q is one of the integers 0, 1 or 2; Y is H 2  or O; or Z, taken with R 1  forms ##STR3## R 1  is hydrogen or alkyl or combined with Z as described above; R 2  and R 3  are, independently, hydrogen, alkyl, alkoxy, aralkoxy, alkanoyloxy, hydroxy, halo, amino, mono- or dialkylamino, carbamoyl or sulfonamido or R 2  and R 3 , taken together are methylenedioxy, ethylenedioxy or propylenedioxy; m is one of the integers 1, 2 or 3; n is one of the integers 0 or 1; or a pharmaceutically acceptable salt thereof are antipsychotic, antidepressant and anxiolytic agents useful in relieving the symptoms of these disease states.

This is a division of application Ser. No. 07/719,886 filed Jun. 21,1991 now U.S. Pat. No. 5,182,292.

BACKGROUND OF THE INVENTION

European Patent Application EP 170,213 discloses a series of glutarimidederivatives of benzodioxan methanamine as antianxiety andantihypertensive agents. Fozard et. al. Br. J. Pharmacol. 90, 273P(1987) disclose8-[4-(1,4-benzodioxan-2-ylmethylamino)butyl]-8-azaspiro[4.5]decane-7,9-dione(MDL 72832) as a selective and stereospecific [(-)-MDL 72832 binds 32times as much as the dextrorotary isomer at the 5-HT_(1A) receptor site]ligand for 5-HT_(1A) receptors. ##STR4##

European Patent EP 236,930 discloses a series of2-substituted-alkyl-1,2-benzisothiazole-3-one 1,1-dioxide derivativesuseful as anxiolytic and antihypertensive agents. Specifically claimedis2-(4-(2,3-dihydro-1,4-benzodiox-2-yl)methylamino)butyl)-1,2-benzisothiazol-3(2H)-one1,1-dioxide. ##STR5##

U.S. Pat. No. 4,910,302 discloses a series of psychotropic polycyclicimides as antianxiety and antipsychotic agents. Of greatest relevance tothe present application are the two compounds indicated below: ##STR6##

U.S. Pat. Nos. 4,921,958, 4,873,331, and 4,882,432 describe adamantylesters, carbonates, ureas, urethans, and reverse amides as anxiolytic,antidepressant and antihypertensive agents. ##STR7##

German Patent Application 1,812,768 discloses a series of1,4-benzodioxan derivatives of structure I, in which R¹ is H, Cl, Me orMeO, R² is H, C₁₋₄ alkyl, benzyl, phenyl, or phenyl substituted by Cl,Me, MeO or CF₃, A¹ is methylene, ethylene, CO, CH₂ CO or CH(OH)CH₂, A²is methylene, ethylene or ethylidene, and Z is S, SO, or SO₂, asvasodilators. ##STR8##

Belgian Patent Application Belg. 636,238 discloses a series of1-(1,4-benzodioxan-2-yl-methyl)-4-phenylpiperidines of formula II,wherein R¹ is H or F, R² is the group (CH₂)_(n) NHCOR³, where n=0 or 1and R³ =alkyl (C₁ -C₇), alkoxy (C₁ -C₇), cyclopropyl, benzyl, phenyl ortrialkoxyphenyl, for the reduction of blood pressure. ##STR9##

Ger. Offen. DE 3,124,366 discloses a series of N-oxacyclylalkylpiperidine derivatives of structure III, in which A is(un)substituted phenylene, R, R¹ and R², R³ =H, or C₁₋₅ alkyl, or R² R³=A or alkylene, R⁴ =H, C₁₋₅ alkyl, aryl, X=O, S, NH, NMe, NBu, Y=O or S,n=1-3, p, q=1,3, p+q=4, as neuroleptics. Representative of thesecompounds is the agent R 4836,1-[1-(benzo-1,4-dioxan2ylmethyl)-4-piperidinyl]benzimidazol-2-onehydrochloride. ##STR10##

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a group of novelantipsychotic/anxiolytic agents of the formula: ##STR11## in which Z is##STR12## where R⁴ is --H or alkyl of 1 to 4 carbon atoms;

q is one of the integers 0, 1 or 2;

Y is H₂ or O; or

Z, taken with R¹ forms ##STR13## R¹ is hydrogen or alkyl of 1 to 4carbon atoms or is combined with Z as described above;

R² and R³ are, independently, hydrogen, alkyl of 1 to 4 carbon atoms,alkoxy of 1 to 4 carbon atoms, aralkoxy of 7 to 12 carbon atoms,alkanoyloxy of 2 to 6 carbon atoms, hydroxy, halo, amino, mono- ordialkylamino in which each alkyl group has 1 to 4 carbon atoms,alkanamido of 2 to 6 carbon atoms or sulfonamido or R² and R³, takentogether are methylenedioxy, ethylenedioxy or propylenedioxy;

m is one of the integers 1, 2 or 3;

n is one of the integers 0 or 1;

or a pharmaceutically acceptable salt thereof.

Of these compounds, the preferred members are those in which Z isdefined as above, R¹ is hydrogen or combines with Z as described above,m is the integer 2, and n, R² and R³ are defined as above. Mostpreferred are those members in which Z is adamantyl or noradamantyl, orZ combines with R¹ as described above, R² and R³ are hydrogen, and n is1.

The pharmaceutically acceptable salts are those derived from suchorganic and inorganic acids as: acetic, lactic, citric, tartaric,succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric,nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.

The compounds of this invention are prepared by conventional methods.For example, the appropriately substituted benzodioxan methanamine iscombined with a suitable acid halide in the presence of an acidscavenger such as diisopropylethylamine in a solvent such asdichloromethane (1), or with a suitable anhydride, followed by a periodof reflux in a high boiling solvent such as xylene, with water removalby means of a Dean-Stark trap (2). The 1,2-benzisothiazol-3(2H)-one1,1-dioxide derivatives may be prepared by reaction of the appropriatelysubstituted benzodioxan methanamine with methyl2-(chlorosulfonyl)-benzoate in the presence of a tertiary amine such asdiisopropylethylamine, followed by treatment of the resulting amide witha base such as dimethylaminopyridine (DMAP) in refluxing xylene (3).##STR14##

Finally, the compounds of the invention may be more generally prepared(4) by reaction of the suitably substituted cyclic amine with theappropriate benzodioxan methyl halide or tosylate in the presence of anacid scavenger such as diisopropylethylamine in a high boiling solventsuch as dimethylformamide. ##STR15##

The bicyclic carboxylic acids described by Z are known compounds or theycan be readily synthesized by one schooled in the art. Adamantane andnoradamantane-1-carboxylic acids are commercially available; ketopinicacid can be prepared from camphorsulfonyl chloride by the method ofBartlett and Knox (Organic Synthesis, Vol 45, p. 55) and can beconverted to apocamphane-1-carboxylic acid by the method described in J.Am. Chem. Soc., 61, 3184 (1939). The benzodioxan methanamines and methylhalides themselves are known compounds, or they can readily be derivedfrom the appropriate salicylaldehyde by the procedure illustrated below:##STR16##

The compounds of this invention possess high affinities for the dopamineD-2 receptor and the serotonin 5-HT_(1A) receptor, and consequently,they are useful as antipsychotic, antidepressant and anxiolytic agentsfor the treatment of a variety of central nervous system disorders suchas depression, paranoia, schizophrenia, anxiety, sleep disorders, sexualdysfunction, addiction, and related problems.

High affinity for the dopamine D-2 receptor was established by thestandard experimental test procedure of Fields, et al., Brain Res., 136,578 (1977) and Yamamura et al., eds., Neurotransmitter Receptor Binding,Raven Press, N.Y. (1978) wherein homogenized limbic brain tissue isincubated with ³ H-spiroperidol and various concentrations of testcompound, filtered and washed and shaken with Hydrofluor scintillationcocktail (National Diagnostics) and counted in a Packard 460 CDscintillation counter. The results of this testing with compoundsrepresentative of this invention are given below.

High affinity for the serotonin 5-HT_(1A) receptor was established bytesting the claimed compound's ability to displace [³ H] 8-OHDPAT(dipropylaminotetralin) from the 5-HT_(1A) serotonin receptor followingthe procedure of Hall et al., J. Neurochem. 44, 1685 (1985). Thisprocedure is employed to analogize this property of the claimedcompounds with that of buspirone, which is a standard for anxiolyticactivity, and, like the compounds of this invention, displays potentaffinity for the 5-HT_(1A) serotonin receptor subtype. The anxiolyticactivity of buspirone is believed to be, at least partially, due to its5-HT_(1A) receptor affinity (Vander Maclen et al., Eur. J. Pharmacol.1986, 129 (1-2) 133-130).

The results of the two standard experimental test procedures describedin the preceding two paragraphs were as follows:

    ______________________________________                                                D-2 Binding      5-HT.sub.1A Binding                                  Compound                                                                              (% Inhibition at 1 μM)                                                                      (% Inhibition at 0.1 μM)                          ______________________________________                                        Example 1                                                                             29%              59% (IC.sub.50 = 107 nM)                             Example 2                 4%                                                  Example 3                45%                                                  Example 4                                                                             97%              96%                                                  Example 5                                                                             52%              92%                                                  ______________________________________                                    

Hence, the compounds of this invention demonstrated high affinity forboth the serotonin 5-HT_(1A) and dopamine D₂ receptor subtypes, and aretherefore useful in the treatment of multi-CNS disorders amenable totreatment with antipsychotic, antidepressant and anxiolytic agents. Assuch, the compounds of this invention may be administered orally orparenterally to a mammal in need of antipsychotic, antidepressant and/oranxiolytic medical treatment in an amount sufficient to alleviate thesymptoms of the disease state.

Applicable solid carriers for the compounds of this invention caninclude one or more substances which may also act as flavoring agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aids, binders or tablet-disintegrating agents or anencapsulating material. In powders, the carrier is a finely dividedsolid which is in admixture with the finely divided active ingredient.In tablets, the active ingredient is mixed with a carrier having thenecessary compression properties in suitable proportions and compactedin the shape and size desired. The powders and tablets preferablycontain up to 99% of the active ingredient. Suitable solid carriersinclude, for example, calcium phosphate, magnesium stearate, talc,sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose,sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxesand ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

The dosage to be used in the treatment of a specific psychosis must besubjectively determined by the attending physician. The variablesinvolved include the specific psychosis or state of anxiety ordepression and the size, age and response pattern of the patient.

The following examples illustrate the production of representativecompounds of this invention.

EXAMPLE 1N-[1-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]tricyclo[3.3.1.1³,7]decane-1-carboxamide

To an anhydrous solution of 3.0 ml (17 mmole) of diisopropylethylamineand 1.2 g (4.9 mmole)1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-aminopiperidine in 150 mlof dichloromethane maintained at 0° C. in an ice/salt water bath wasadded 0.99 g (5.0 mmole) of adamantane-1-carbonyl chloride in 75 ml ofdichloromethane. The mixture was allowed to come to room temperature andstirred overnight. It was then washed with 300 ml each of water,saturated aqueous sodium bicarbonate, saturated sodium chloridesolution, dried over magnesium sulfate, filtered and concentrated invacuum. The crude residue was filtered through 75 g of silica gel, using2.5% methanol in dichloromethane as eluant, and the product-containingfractions evaporated to give 2.3 g of yellow oil. This was dissolved indichloromethane and brought to a boil. Isopropanol was slowly added toreplace the boiling dichloromethane, then 5.0 ml of 4N isopropanolic HClwas added. Upon cooling, 1.67 g (75% yield) of the title compound,monohydrochloride, hemihydrate, (m.p. 246°-250° C.) precipitated as awhite powder.

Elemental Analysis for: C₂₅ H₃₄ N₂ O₃.HCl.1/2 H₂ O; Calcd: C, 65.84; H,7.95; N, 6.14; Found: C, 65.75; H, 7.96; N, 6.19.

EXAMPLE 2 3a, 4, 4a, 6a, 7,7a-Hexahydro-2-[1-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]-4,7-etheno-1H-cyclobut[f]isoindole-1,3(2H)-dione

1-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methyl]-4-aminopiperidine (1.0 g,4.0 mmole) andhexahydro-4,7-etheno-1H-cyclobut[f]isobenzofuran-1,3-(2H)-dione (0.88 g,4.3 mmole) were combined in 40 ml of xylene and the mixture was refluxedfor 44 hours under nitrogen, with water removal being accomplished bymeans of a Dean-Stark trap. Upon cooling, the mixture was columnchromatographed on 75 g of silica gel with toluene, thendichloromethane, and finally 2.5% methanol/dichloromethane as eluant.The product-containing fractions were combined and concentrated invacuum, and the residue (1.38 g) crystallized from 50 ml of isopropanolwith the addition of 10 ml of 4N isopropanolic HCl.to give 1.3 g of thetitle compound as a white solid, monohydrochloride, quarter hydrate,m.p. 262°-272° C.

Elemental Analysis for: C₂₆ H₂₈ N₂ O₄.HCl.1/4 H₂ O; Calcd: C, 65.95; H,6.27; N, 5.91; Found: C, 65.84; H, 6.38; N, 5.84.

EXAMPLE 32-[1-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]-1,2-benzoisothiazol-3(2H)-one1,1-dioxide

1-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methyl]-4-aminopiperidine (1.3 g,5.2 mmole), diisopropylethylamine (6.8 ml, 39 mmole) and methyl2-(chlorosulfonyl)benzoate (1.6 g, 6.8 mmole) were combined in 80 ml ofdichloromethane and the mixture was stirred at room temperature undernitrogen for 3 hours. The mixture was then washed with saturated aqueoussodium bicarbonate, dried over magnesium sulfate, filtered andconcentrated in vacuum. The residue was column chromatographed on 100 gof silica gel with first 30%, then 50% ethyl acetate/pet ether aseluant. The product-containing fractions were combined and concentratedin vacuum to give 1.88 g of the intermediate sulfonamide, with theexpected NMR. This was redissolved in 40 ml of xylene and 0.60 g ofdimethylaminopyridine added. This mixture was refluxed under nitrogenfor 4 days. It was allowed to cool to room temperature and filteredthrough 75 g of silica gel, using 2.5% methanol/dichloromethane tocompletely remove the product. The product was concentrated in vacuumand the residue crystallized from isopropanol with the addition of 4Nisopropanolic HCl to give 1.21 g of the title compound as a white solid,monohydrochloride, m.p. 224°-230° C.

Elemental Analysis for: C₂₁ H₂₂ N₂ O₅ S.HCl; Calcd: C, 55.93; H, 5.14;N, 6.21; Found: C, 55.85; H, 5.06; N, 6.25.

EXAMPLE 43-[[1-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]decahydro-2H-1,5-methano-6,7,9-methenopentaleno[1,2-d]azepine-2,4(3H)-dione

1-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methyl]-4-aminomethylpiperidine(1.38 g, 5.26 mmole) anddecahydro-1,5-methano-6,7,9-methenopentaleno[1,2-d]oxepine-2,4(1H,5H)-dione(1.68 g, 7.3 mmole) were combined in 100 ml of xylene and the mixturewas refluxed for 48 hours under nitrogen, with water removal beingaccomplished by means of a Dean-Stark trap. Upon cooling, the mixturewas concentrated in vacuum and the residue column chromatographed on 50g of silica gel with 1.5% methanol/dichloromethane as eluent. Theproduct-containing fractions were combined and concentrated in vacuum,and the residue crystallized from isopropanol with the addition of 4Nisopropanolic HCl to give 0.53 g of the title compound as a white solid,monohydrochloride, m.p. 248°-252° C.

Elemental Analysis for: C₂₉ H₃₄ N₂ O₄.HCl; Calcd: C, 68.16; H, 6.90; N,5.48; Found: C, 67.87; H, 6.99; N, 5.35.

EXAMPLE 5N-[[1-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]tricyclo[3.3.1.1³,7]decane-1-carboxamide

To an anhydrous solution of 9.0 ml (52 mmole) of diisopropylethylamineand 1.7 g (6.5 mmole)1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-aminomethylpiperidine in125 ml of dichloromethane maintained at 0° C. in an ice/salt water bathwas added dropwise over 40 minutes a solution of 1.5 g (7.8 mmole) ofadamantane-1-carbonyl chloride in 50 ml of dichloromethane. The mixturewas then poured onto 400 ml of ice, the ice allowed to melt and theorganic phase removed in a separatory funnel. After dilution to 400 mlwith additional dichloromethane, the organic phase was washed with 400ml each of saturated aqueous sodium bicarbonate, saturated sodiumchloride solution, dried over magnesium sulfate, filtered andconcentrated in vacuum. The crude residue (3.6 g) was flashchromatographed on 250 g of silica gel using 2.5% methanol indichloromethane as eluant, and the product-containing fractionsevaporated to give 2.1 g of free base. This was dissolved indichloromethane and brought to a boil. Isopropanol was slowly added toreplace the boiling dichloromethane, then 6.0 ml of 2N isopropanolic HClwas added. Upon cooling, 1.88 g (47% yield) of the monohydrochloride ofthe title compound (m.p. 254°-256° C.) precipitated as white crystals.

Elemental Analysis for: C₂₆ H₃₆ N₂ O₃.HCl; Calcd: C, 67.73; H, 8.09; N,6.08; Found: C, 67.55; H, 8.06; N, 5.85.

What is claimed is:
 1. A method for relieving the symptoms of apsychosis, depression or anxiety which comprises administering to apatient in need thereof, an antipsychotic, antidepressant or anxiolyticamount of a compound of the formula: ##STR17## in which Z is ##STR18##where R⁴ is --H or alkyl of 1 to 4 carbon atoms;q is one of the integers0, 1 or 2; Y is H₂ or O; Z, taken with R¹ forms ##STR19## R¹ is hydrogenor alkyl of 1 to 4 carbon atoms or combined with Z as described above;R² and R³ are, independently, hydrogen, alkyl of 1 to 4 carbon atoms,alkoxy of 1 to 4 carbon atoms, aralkoxy of 7 to 12 carbon atoms,alkanoyloxy of 2 to 6 carbon atoms, hydroxy, halo, amino, mono- ordialkylamino in which each alkyl group has 1 to 4 carbon atoms,alkanamido of 2 to 6 carbon atoms or sulfonamido or R² and R³, takentogether are methylenedioxy, ethylenedioxy or propylenedioxy; m is oneof the integers 1, 2 or 3; n is one of the integers 0 or 1;or apharmaceutically acceptable salt thereof.